Fracture risk assessment is integral to the diagnosis and management of osteoporosis, a devastating clinical condition of which over 40 million Americans are at risk. Due to limitations in areal BMD measures obtained from 2D DXA scans - the current clinical standard for diagnosis of osteoporosis - it has recently become clear that those at risk of osteoporotic fracture need to be better identified. A 3D biomechanics-based technique, which we term Biomechanical Computed Tomography (BCT), addresses this need through a combination of engineering finite element analysis, 3D quantitative computed tomography (QCT), and bone fracture biomechanics. The main outcome parameter of BCT is an estimate of the biomechanical risk of a bone fracture that accounts for such factors as the patient's 3D bone geometry and distribution of bone density, body-weight, height, trochanteric soft tissue thickness (for hip fractures), muscle moment arm (for spine), and the age-related risk of sustaining an overload event (such as a fall or lifting of a heavy object with back bent). In the larger context of translating BCT to clinical practice, we seek in this Phase II SBIR project to test the overall hypothesis that BCT is a better predictor of osteoporotic fracture than is areal BMD, for both hip and spine fracture and for both women and men. In Phase I of this project, we successfully applied this technique to explain observed age-related trends in hip fracture rates. For Phase II, we plan in our first Aim to refine our BCT technique to produce a fully automated, highly reliable and highly accurate software suite with the capability to analyze CT scans acquired for any medical test with coverage of the hip and/or spine without an external calibration phantom. For Aim 2, in order to ensure optimal prediction of clinical fractures, we will further refine our overall BCT process by calibrating results from the two cohorts (the Mayo Clinic cohort of 750 men and women in Rochester MN, and the MrOS cohort of 3,500 men in six U.S. locations). Issues to be resolved in this calibration process include determining optimal methods for measuring soft tissue thickness, muscle moment arms, and spine loading. This analysis will also enable us to calibrate our function for age- related risk of sustaining an overload event, which may depend on both fracture type (hip vs. spine) and sex. In Aim 3, we will compile normative data for BCT outcomes, critical information for interpretation of clinical results. Having refined and calibrated the overall BCT technique and identified the most successful BCT predictors of clinical fracture in the Mayo and MrOS cohorts, we will proceed in Aim 4 to test the validity of these predictors in a fully prospective manner, without any further modification of the BCT technique. For this, we will analyze the AGES cohort of 5,500 women and men in Reykjavik, Iceland, for incident hip and spine fracture. Taken together, this multi-cohort international validation study will provide new insight into osteoporotic fracture etiology, important advancements for the BCT method, and a thorough evaluation of BCT clinical performance. This project should therefore have a significant impact on osteoporosis research and clinical practice. PUBLIC HEALTH RELEVANCE: Statement of Relevance This project will provide clinical validation to Biomechanical Computed Tomography, a promising clinical alternative to DXA for the diagnosis of osteoporosis. Successful translation of BCT to clinical practice has the potential to greatly improve non-invasive assessment of fracture risk, which would represent an important advance in the preventative care and treatment of osteoporosis.